Project Summary/Abstract The aggregation of misfolded disease-related proteins is a hallmark of many different neurodegenerative diseases including Alzheimer's, Huntington's, Parkinson's and ALS. While the role of these aggregates in pathogenesis is unclear, it is obvious that a better understanding of the mechanism of inclusion formation and clearance is critical to understanding the etiology and development of potential therapies for these devastating neurodegenerative disorders. Aggregates associated with conformational neurodegenerative diseases can be classified into amyloid and non-amyloid aggregates. A and mutant Huntingtin (mHtt) both form amyloid aggregates while SOD1 and TDP-43 form non-amyloid aggregates. Recent studies have shown that misfolded proteins are actively sequestered into Quality Control (QC) compartments. Studies from the Frydman lab have shown that amyloid proteins, including highly expanded mHtt, are sequestered into the IPOD whereas normal misfolded proteins are transported to the Q-body or JUNQ, depending on proteasome impairment. However, it remains unclear whether this differential sorting is a result of an inherent difference in amyloid protein sorting or if the mutation is causing the mHtt to be organized to a different QC compartment within the cell. Additionally, it is unknown which QC compartment is the site of sequestration for non-amyloid neurodegenerative disease-related proteins. Understanding the basis for these triage decisions will further our knowledge of the mechanism of inclusion formation and the function of inclusion bodies within the cell. It is also critical to understand the fate of these QC inclusions containing mutant disease-related proteins. A better understanding of the persistence, refolding or clearance of these inclusions will provide the opportunity for novel therapeutic targets for neurodegenerative proteinopathies. A major goal of this research is to determine how amyloid and non-amyloid disease-related proteins are sequestered to QC compartments and how these compartments are cleared by the cell. Here we propose to ascertain the site of protein sequestration for amyloid and non-amyloid disease-related proteins as well as how the cell eliminates QC inclusions. The results of this project will inform on how different misfolded disease- related proteins are processed by the cell which can provide insight into novel shared therapeutic targets for numerous neurodegenerative conformational disorders.